Vinca alkaloids, originally isolated from the periwinkle plant [Vinca rosea Linn., now Cantharanthus roseus (L.) G. Don] are a family of indole-indoline dimeric compounds that contain a four-ring system containing an indole linked to a five-ring system containing an indoline. Two of those natural alkaloids, vinblastine and vincristine, are important clinical agents in the treatment of leukemias, lymphomas and testicular cancer.
The semi-synthetic vinca alkaloid, vinorelbine, has activity against lung cancer and breast cancer, and vindesine is used to treat lung cancer and acute leukemia and less often for melanoma, and breast cancer. [Goodman & Gilman's The Pharmaceutical Basis of Therapeutics, Hardman et al. Eds., 9th ed., McGraw-Hill, 1257-1260, 1996] The 19′,20′-anhydrovinca alkaloids (anhydrovinca alkaloids) are also active in treating the above diseases, albeit, they are usually somewhat less potently cytotoxic. Thus, the semi-synthetic anhydrovinca alkaloid, vinorelbine, has activity against lung cancer and breast cancer, and anhydrovinblastine is active as is shown hereinafter. Anhydrovincristine and anhydrovindesine are also cytotoxic.
 R1R2R3Vinblastine (1)—CH3 Vincristine (2) Vindesine—CH3—OH
 nR1R2R3Vinorelbine1—CH3 Anhydro- vinblastine (4)2—CH3 Anhydro- vincristine2 Anhydro- vindesine2—CH3—OH
Vinblastine (1) and vincristine (2) represent the most widely recognized members of the vinca alkaloids as a result of their clinical use as antitumor drugs. [Noble et al., Ann. N.Y. Acad. Sci. 1958, 76:882; Noble, Lloydia 1964, 27:280; Svoboda et al., J. Am. Pharm. Assoc. Sci. Ed. 1959, 48:659; Moncrief et al., J. Am. Chem. Soc. 1965, 84:4963; Review:: Neuss et al., In The Alkaloids; Brossi et al Eds.; Academic: San Diego, 1990; Vol. 37:229] Originally isolated in trace quantities from Cantharanthus roseus (L.) G. Don, [Noble et al., Ann. N.Y. Acad. Sci. 1958, 76:882; Noble, Lloydia 1964, 27:280; Svoboda et al., J. Am. Pharm. Assoc. Sci. Ed. 1959, 48:659] their biological properties were among the first to be shown to arise from inhibition of microtubule formation and mitosis that today is still regarded as one of the more successful drug targets for the treatment of cancer. [Reviews: Neuss et al., In The Alkaloids; Brossi et al Eds.; Academic: San Diego, 1990; Vol. 37:229; Pearce, H. L. In The Alkaloids; Brossi et al. Eds.; Academic: San Diego, 1990; Vol. 37:145; Borman et al., In The Alkaloids; Brossi et al. Eds.; Academic: San Diego, 1990; Vol. 37:133; Fahy Curr. Pharm. Design 2001, 7:1181; Kuehne et al., In The Alkaloids; Brossi et al. Eds.; Academic: San Diego, 1990; Vol. 37:77; Potier, J. Nat. Prod. 1980, 43:72; Kutney, Nat. Prod. Rep. 1990, 7:85; Kutney, Synlett 1991, 11; (e) Kutney, Acc. Chem. Res. 1993, 26:559; For recent studies, see: Kuehne et al., Org. Biomol. Chem. 2003, 1:2120; Miyazaki et al., Org. Lett. 2007, 9:4737].
The vinca alkaloids, alone or combined with other anti-neoplastic compounds such as cisplatin, bleomycin and the like, are particularly effective in treating a variety of cancerous conditions and are the medications of choice for those treatments. However, multiple drug resistance (MDR) of the treated cells can lead to a loss of efficacy of the drugs in treatment. Extensive research is being carried out to overcome the problem of MDR so that the once effective treatments can be continued as needed.
The inventor and his research group recently utilized a one-pot, two-step biomimetic Fe(III)-promoted coupling of vindoline (3) with catharanthine (4) in the total synthesis of
vinblastine and reported its extension to the preparation of a series of related natural products and key analogues. [Ishikawa et al., J. Am. Chem. Soc. 2008, 130:420; Ishikawa et al., J. Am. Chem. Soc. 2009, 131:4904] Although key mechanistic insights into this coupling [Ishikawa et al., J. Am. Chem. Soc. 2008, 130:420; Ishikawa et al., J. Am. Chem. Soc. 2009, 131:4904; Vukovic et al., Tetrahedron 1988, 44:325; for an analogous electrochemical coupling (0.6 V in buffer; NaBH4) to provide anhydrovinblastine, see: Gunic et al., J. Chem. Soc., Chem. Commun. 1993, 1496; For an enzymatic coupling, see: Sagui et al., Tetrahedron 2009, 65, 312; For additional seminal studies on the Fe(III)-coupling to provide anhydrovinblastine, see Szantay et al., Tetrahedron 1991, 47:1265; Sundberg et al., Tetrahedron 1998, 54:6259] and subsequent olefin oxidation [Ishikawa et al., J. Am. Chem. Soc. 2009, 131:4904; Sakamoto et al, JP 04164087 (Chem. Abstr. 1992, 117:192139); Tan et al., U.S. Pat. No. 5,037,977 (Chem. Abstr. 1990, 113, 6663)] have been disclosed in the studies to date, the unusual differences in the diastereoselectivity of the Fe(III)-promoted coupling (single natural C16′ diastereomer at 25° C. in aqueous buffer) and the more traditional Polonovski fragmentation [Potier et al., J. Chem. Soc., Chem. Commun. 1975, 670; Langlois et al., J. Am. Chem. Soc. 1976, 98:7017; Sundberg et al., Tetrahedron 1992, 48:277; Kutney et al., Heterocycles 1975, 3:639; Kutney et al., Helv. Chim. Acta 1976, 59:2858] (5:1 at −78° C. or 1:1 at 0° C. in CH2Cl2) or 3-chloroindolenine-based couplings suggests that there are mechanistic features of the former reaction that are not yet well understood and that affect the resulting C16′ stereochemistry. [For additional approaches to effecting analogous couplings, see: Magnus et al., J. Am. Chem. Soc. 1990, 112:8210; Magnus et al., J. Am. Chem. Soc. 1992, 114:10232; Kuehne et al., J. Org. Chem. 1991, 56:513; Bornmann et al., J. Org. Chem. 1992, 57:1752; Kuehne et al., J. Org. Chem. 1987, 52:4340; Schill et al., Tetrahedron 1987, 43:3765; Yokoshima et al;., J. Am. Chem. Soc. 2002, 124:2137; Kuboyama et al., Proc. Natl. Acad. Sci. USA 2004, 101:11966]
N-methyl catharanthine fails to couple with vindoline under either set of conditions, indicating that both approaches require the free indole NH and suggesting that they both may potentially proceed through a common azabenzfulvene intermediate (equation 1, below). Yet, the two approaches proceed with the distinct stereochemical outcomes.

In the case of the Fe(III)-promoted coupling, the attack by vindoline formally occurs with clean inversion of the stereochemistry at the reacting C16 center of the C16-C21 bond undergoing cleavage and it has been suggested that initial radical cation formation occurs at the basic tertiary amine. [Vukovic et al., Tetrahedron 1988, 44:325; For an analogous electrochemical coupling (0.6 V in buffer; NaBH4) to provide anhydrovinblastine, see: Gunic et al., J. Chem. Soc., Chem. Commun. 1993, 1496; For an enzymatic coupling, see: Sagui et al., Tetrahedron 2009, 65, 312; For additional seminal studies on the Fe(III)-coupling to provide anhydrovinblastine, see Szantay et al., Tetrahedron 1991, 47:1265; Sundberg et al., Tetrahedron 1998, 54:6259]
Disclosed hereinafter is the first report of the examination of catharanthine substituent effects on the coupling reaction, establishing the importance of its C16 methyl ester and the electronic impact of a catharanthine C10 indole substituent on biologic activity. An unexpected finding was the enhanced activity of the 10′-fluorinated vinca alkaloids compared to their unsubstituted parental vinca alkaloid compounds (10′-hydrido vinca alkaloid compounds), and particularly the enhanced activity against multiple drug resistant cells. The mechanistic implications are also noted and discussed.